Rheumatoid arthritis (RA) is a chronic, systemic, inflammatory autoimmune disease targeting the synovium, the tissue that lines the joints. It is associated with increased risk of infection (pulmonary in particular), osteoporosis, and cardiovascular disease. Afflicting about 1 % of the population worldwide, RA causes pain, swelling, stiffness, and loss of motion in the joints, and, if unchecked, can cause irreversible joint damage, severe functional impairment, and premature death. Since RA thus far has no cure, most current therapies aim to slow disease progression and in recent years this has been accomplished with Disease Modifying Anti- Rheumatic Drugs (DMARD). While the anti-TNF1, anti-IL-12, and more recently anti-IL-6 DMARD compounds have successfully treated RA patients, a number of problems such as an injectable route of delivery and the development of neutralizing antibodies have lead to the search for small molecule compounds that can control RA symptoms when delivered as a daily pill. Cognosci has identified a novel series of anti-inflammatory apoE-mimetic peptides that suppress production of TNF1, IL-12, IL-6, and nitric oxide in vitro and in vivo, and thus have many of the properties necessary for an RA therapy. Using funds from a previous Phase I SBIR grant, we demonstrated that one of these peptides, COG133, inhibited production of cytokines and matrix metalloprotease (MMP) enzymes in primary human synovial fibroblasts. Furthermore, COG133 reduced disease symptoms and improved histological outcome in the murine collagen induced arthritis (CIA) model of RA. Recently, we have determined that COG133 acts by binding to and antagonizing the actions of the protein SET, also known as Inhibitor-2 of Protein Phosphatase 2A (I2PP2A). COG133's efficacy at reducing swelling, clinical scores, and cartilage damage in the paws of treated mice, coupled with COG133-mediated lowering of cytokine and MMP production from synovial cell fibroblasts, validates SET antagonism, and the associated PP2A activation, as a bona fide target for the development of novel RA therapeutics. We now propose to develop assays to enable high throughput screening to identify novel small molecule inhibitors of SET that will allow for development of an orally active anti-RA therapy that will inhibit multiple inflammatory pathways by antagonism of a single target. 1 PUBLIC HEALTH RELEVANCE: Rheumatoid arthritis (RA) is a chronic, systemic, inflammatory autoimmune disease targeting the synovium, the tissue that lines the joints. It afflicts about 1 % of the population worldwide and causes pain, swelling, stiffness, and loss of motion in the joints, and, if unchecked, can cause irreversible joint damage, severe functional impairment, and premature death. Since RA thus far has no cure, most current therapies aim to slow disease progression and in recent years this has been accomplished with Disease Modifying Anti- Rheumatic Drugs (DMARD). While the anti-TNF1, anti-IL-12, and more recently anti-IL-6 DMARD compounds have successfully treated RA patients, a number of problems such as an injectable route of delivery and the development of neutralizing antibodies have lead to the search for small molecule compounds that can control RA symptoms when delivered as a daily pill. Cognosci has identified a novel series of anti-inflammatory peptides that suppress reduce disease symptoms and joint damage in an mouse model of RA. These data validate that a small compound that mimics the larger peptides could work as a daily therapy for RA that would be taken as a pill rather than injections. In this we propose to develop assays that will help to identify these novel drug leads that can be used to develop a new anti-RA therapy.